Epigenetic changes in estrogen receptor β gene in atherosclerotic cardiovascular tissues and in-vitro vascular senescence

Abstract

Epigenetic changes marked by DNA methylation have been proposed to play a role in age-related disease. We investigated DNA methylation changes in cardiovascular atherosclerotic tissues and in-vitro vascular senescence in the promoter of estrogen receptor beta gene, which has essential roles in vascular function. Coronary atherosclerotic tissues showed higher methylation levels (28.7%) than normal appearing arterial (6.7%-10.1%) and venous tissues (18.2%). In comparing estrogen receptor beta methylation between plaque and non-plaque regions in ascending aorta, common carotid artery, and femoral artery of two patients, the plaque lesions showed consistently higher methylation levels than non-plaque regions. Passage-dependent increased estrogen receptor beta methylation was observed in three of six human aortic endothelial or smooth muscle cell lines cultured in-vitro to vascular senescence. Estrogen receptor beta expression in these vascular cell lines was significantly activated by DNA-methyltransferase inhibition. This activity was augmented by histone deacetylase inhibition. These findings provide evidence of epigenetic dysregulation of estrogen receptor beta in atherosclerosis and vascular aging. We suggest that focal epigenetic changes in estrogen receptor beta contribute to the development of atherosclerosis and vascular aging.

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

“…in the 5' region of ESR2, FADS2 and TFPI2) (14)(15)(16). Log 2 r/g values in CAs and AAs were -2.72, -1.40 for ESR2, and -3.14, -2.18 for FADS2, respectively, with a p-value of <0.05 in both cases.…”

Aging and epigenetic drift: a vicious cycle

“…In tis sues with relatively little cellular turnover and in which carcinogen exposure is relatively low and spontaneous mutations relatively few, focal proliferation itself leads to pathology, as in coronary ath erosclerosis. Interestingly, aberrant methylation of genes such as ERa and ERb has been observed in atherosclerotic plaques (78,79). In tissues regularly exposed to carcinogens, such as lung or gas trointestinal tract, the agerelated clonal expansion might allow oncogenic mutations to transform cells, resulting in fullblown malignancy.…”

Aging and Atherosclerosis

“…99 In particular, hypermethylation of ER␣ leads to reduced expression that might contribute to VSMC proliferation in early atherosclerosis, 100,102 whereas hypermethylation of ER␤ appears in advanced lesions and is involved in vascular senescence. 101 A number of miRNAs are upregulated in atherosclerosis and/or regulate processes associated with aging, such as cell proliferation, apoptosis, or senescence (summarized in Figure 3). For example, miR-21 is increased after vessel injury, promotes VSMC proliferation and regulates VSMC survival through modulation of phosphatase and tensin homolog and B-cell lymphoma-2 (Bcl-2) expression.…”